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Pharmaceutical Products –Pharmaceutical Products –Extractables & Leachables

CConcept

ByDr. A. J Vaidya

E il id @ l ti l l ti iEmail: [email protected]

EXTRACTABLE AND LEACHABLEEXTRACTABLE AND LEACHABLE

REFERENCES:

EMEA – Guideline on Immediate Plastic Packaging MaterialsPQRI Guide – Suggestions to FDA for Extractables and LeachablesExtractables and LeachablesPh.Eur. Appendices 3.1.4 & 3.1.5 for Polyethylene with and without additivesUSP General Chapters <1663> on Extractables and <1664> on Leachables


Extractables:Extractables:

Compounds that are removed from glassCompounds that are removed from glass, elastomeric, plastic components or coating of the container closure system in the presence y pof an appropriate solvent(s) under laboratory conditions.Extractable are potential leachable.


Leachables:Leachables:

Compounds that migrate from glassCompounds that migrate from glass elastomeric, plastic components or coatings of the container closure system as a results yof contact with formulation under normal condition of use.Leachables are typically a subset of extractables.


Concerns for leachablesConcerns for leachables

Patient SafetyPatient SafetyInterference with drug product assayInterference with diagnostic testInterference with diagnostic testUnacceptable levelReaction with active ingredients orReaction with active ingredients or excipients

EXTRACTABLE AND LEACHABLERisk for LeachableDegree of Concern Likelihood of packaging component-DossageDegree of Concern Associated with route of Administration

Likelihood of packaging component DossageForm interaction

High Medium LowHighest Inhalation Aerosols &

Solutions- Injections & Injectable Susp.

SterilePowder & Powders per injections

High Ophthalmic Solution & Suspensions- Transdermal ointment &

patches- Nasal Aerosols & Sprays

Low Topical Solutions & Suspensions

Topical & oral powders

Oral tablets &Suspensions

Topical & lingual Aerosols. Oral Solutions & Suspensions

powders tablets & oral capsules

EXTRACTABLE AND LEACHABLESources for LeachablesIn-process single use systems

i l bi t f d t i t di tsingle use bioreactors for product intermediatesIV bags, carboys, Filters, Tubing & gaskets etc.

Primary packaging components:y p g g psyringes, ampoules, vials and bottlesPlastic/Metal Containers, Closure (Screw caps rubber Stoppers)Closure (Screw caps, rubber Stoppers)

Secondary packaging Componentscardboard containers (Cartons)OOverwrapsLabels (with Adhesive & inks)

Tertiary packaging Materialsy p g gCorrugated Boxes, Pallets


E& L Testing ApproachE& L Testing ApproachIdentify & develop a profile of Extractables using appropriate methodsQuantify the level of extractables that will be studied as leachablesDevelop a Program to monitor leachablesDevelop a Program to monitor leachables during product stabilityEstablish specifications & Acceptance criteriap p


Appropriate Extraction procedureAppropriate Extraction procedureCritical to select appropriate temperature, time & pH conditionsExtraction SolventsSolvents of varying polarity i.e highly polar to non polarnon polar Drug product vehicle

EXTRACTABLE AND LEACHABLEEXTRACTABLE AND LEACHABLEMajor Test Categories

Non volatile organic CompoundsNon volatile organic CompoundsSemi Volatile organic compoundsVolatile organic compoundsVolatile organic compoundsTrace metalsNon Specified tests

- Conductivity- pH- TOC


Analytical technique usedy qGC/MS & GC-HS-MSLC/MSLC/PDAGC/FIDC /O S/ SICP/OES/MSFTIRICIC

EXTRACTABLE AND LEACHABLE

Desirable information to obtain from SuppliersppThe base elastomeric/polymeric material (e.gHDPE, butyl rubber etc.)The Additive compositionPolymerization process plus associated curing agentsagentsFabrication process additivesCleaning/washing processg g pStorage/shipping environments for finished components


Consideration in packaging component selectionp g g p

Components containing source of known potent carcinogens or mutagens should be avoided e.g

Polynuclear Aromatic HydrocarbonsPolynuclear Aromatic HydrocarbonsN-nitrosoamines2-marcapto benzothiazole (2-MBT)p ( )

EXTRACTABLE AND LEACHABLETop 10 reasons why controlled extraction studies are

neededT k i f d l ti f t i l1. To make an informed selection of materials

2. To meet regulatory expectations3 To control leachables3. To control leachables4. To control material from lot to lot5. To correlate extractables data to leachables6. To evaluate safety of materials7. To predict worst case of end of shelf life

leachables8. To qualify packaging materials9 To obtain a comprehensive extractable profile9. To obtain a comprehensive extractable profile10. Compendial testing does not provide

applicable data


Controlled Extraction ProcessSolvent Selection

Range of polarities (e.g water, MDC, hexane, IPA, Heptane)Similar Extracting property to drug product vehiclevehicleRelatively non-reactiveHigh purityg p yEasily & safely handledReadily available


Extraction Conditions

Need to optimize temp. & time.Vigorous but not so aggressive as toalter the quantitative nature of extraction profile


Multiple Extraction Techniquep qSoxhletRefluxASEMicrowave Digestion


Acceptance criteria for Extractablep

Confirmation of extractables identifiedA quantitative limit for specific/identified/unidentified extractables (Applicable when used as a test in QC for CCS(Applicable when used as a test in QC for CCS components release criteria)


Leachable Testing goalsg gTo help establish an extractables / leachablescorrelation.To understand the trend in leachables level over shelf lifeTo determine maximum leachables level up toTo determine maximum leachables level up to proposed shelf lifeTo support a comprehensive safety evaluation of drug productTo establish leachables specification & Acceptance criteriaAcceptance criteria


Leachable- Testing Recommendationsg

Analytical Method should be based on those used in controlled extraction studiesTesting should be guided by Analytical Evaluation threshold (AET) which is based onEvaluation threshold (AET) which is based on accepted safety concern thresholdA Comprehensive correlation between extractable & leachables profile should be established


Threshold Conceptp

PQRI working group recommended a two tiered qualification strategy for leachables

Safety Concern threshold (SCT)Qualification Threshold (QT)Qualification Threshold (QT)


SCT: The safety concern threshold is the ythreshold below which a leachable would have a dose so low as to present negligible safety concerns from carcinogenic & non carcinogenicconcerns from carcinogenic & non carcinogenic toxic effect.

QT: A qualification threshold is a threshold below which a given non-carcinogenic leachables is not considered for toxicological assessments unlessconsidered for toxicological assessments unless the leachable present SAR concerns

EXTRACTABLE AND LEACHABLEEXTRACTABLE AND LEACHABLEOrally Inhaled Drug Products (OINDP)

SCT = 0 15 µg/day for organic leachableSCT = 0.15 µg/day for organic leachableQT = 5µg/day for organic leachableAET derived directly from SCTAET derived directly from SCT

Note: These threshold are currently applied to inhalation drug products only.


AET- The Analytical Evaluation Threshold (AET) is y ( )defined as the threshold at or above which one should identified & Quantify a particular extractable and/or leachableextractable and/or leachable.

AET to be considered as an acceptance criteria toAET to be considered as an acceptance criteria to conclude weather toxicological assessment needed for a particular leachable.

EXTRACTABLE AND LEACHABLEExample AET Calculation:Example AET Calculation:Product: Ophthalmic SolutionMax daily dose: 1 drop in two eyes = 0.025 ml x 2 = 0.050 mlml/container = 5mlml/container 5mlDose/ Container = 100

60µg/day x 100 dose/containerEstimated AET = ----------------------------------------- = 6000 µg/container6000 µg/container

1 dose/day

6000µg/day x 100 dose/container Estimated AET = =Estimated AET = ----------------------------------------- = 1200 µg/ml (ppm)

5 ml/containerUncertainty factory = Estimated AET X 0.5 = 1200 µg/ml X 0.5 = 600 / l600 µg/mlFinal AET = Estimated AET – Uncertainty factory

= 1200 µg/ml - 600 µg/ml = 600 µg/ml (ppm)


EMEA guideline on the limit of genotoxic g gimpurities

- The acceptance limits for daily intake of t i i iti 5 10 20 d 60 /dgenotoxic impurities are 5,10, 20, and 60 µg/day

based on duration of exposureDuration of Exposure

Si l ≤ 1 ≤3 h ≤6 ≤12Single Dose

≤ 1 month

≤3 month ≤6month

≤12month

Allowable 120 µg 60 µg 20 µg 10 µg 5 µgAllowable daily intake

120 µg 60 µg 20 µg 10 µg 5 µg

- However SCT for MDIs & OINDPs is 0.15 µg/day

EXTRACTABLE AND LEACHABLELeachable Evaluation Summary

1. List all packaging components to be studied for extractable2. Obtain max possible information from supplier e.g COAs,

MSDS open part DMF list of potential leachableMSDS, open part DMF, list of potential leachable3. Optimize analytical process parameters to generate

extractables profile4. Perform controlled extraction study on each component to y p

generate extractables profile5. Identify the extractables observed using technique e.g mass

spectrometry6. Use appropriate reference compound to report extractables6. Use appropriate reference compound to report extractables

quantitatively7. Check the suitability of methods used in extractable study for

evaluation of Drug product leachables8 If necessary modify the methods however this may lead to8. If necessary modify the methods, however this may lead to

regeneration of extractable profile9. Leachables study should be guided by an AET that is based

on accepted SCT.S iti it f th th d f d t ti & tifi ti f10. Sensitivity of the method for detection & quantification of leachable at the level of AET is very important.

11. To achieve required sensitivity sample preparation may include liquid-liquid extraction, SPE or volume reduction f ll d b Ch t h A l i

Cont.…Cont.…12. Leachables to be treated in two separate categories

a. Target compound: s known to be present in the opackaging materials, standards available.p g g ,

b. Unspecified: generated through controlled extraction study13. Set the specifications or acceptance criteria based on

final AETfinal AET.14. Validated the Method to be used for leachable profile15. The validation can be performed on drug product itself or

simulated drug product vehicle.g p16. Validation parameter: Specificity, Linearity, LOQ,

Accuracy, Precision & Robustness17. Validation using simulated drug product vehicle can be

used as a universal method validationused as a universal method validation.18. Study specificity & accuracy for each drug product under

investigation.19. Establish co-relation between leachable profile &

extractable profile generated using validated method.

Cont...Cont...20. Any leachable found above AET should be identified for

possible structure.21. Any leachable found above Qualification Threshold (QT)

shall be assessed for toxicity.22. Toxicological assessment using prediction software's

such as “DEREK” are accepted by FDA23. Evaluate Drug product for leachables throughout

stability studies.24. 3 lot minimum recommendation.25. The intervals can be at least initial, 3M, 6M, 12 M & end of

shelf life.26. Conclude about the safety assessment with respect to

leachables.


Identification of Extractable:

No MS database available for polymer specific impuritiesStd NIST/Weily MS database helps identify the probable chemical compound seen asprobable chemical compound seen as extractableMS database available only for GC-MS & not for LC-MSVolatile & Semi-volatiles analyzed by GC-HS-MS & GC-MS can be identifiedMS & GC-MS can be identifiedThe data gives only probable identification

EXTRACTABLE AND LEACHABLE

Approach to tackle the unknowns in LC-PDA-MSpp

Map the extractableUse a reference compound from known additives or based on literatureCharacterize each extractable compound byCharacterize each extractable compound by RRT, UV Scan, UV maxima and MassThe leachable is confirmed only if it matches ywith all three identification characters. Quantify all unidentified using a Reference C dCompound


MISCONCEPTIONS:Correlating Leachable with Related SubstancesAdditives listed in EP/USP Monographs are considered as only leachablesToxicity studies required for each leachableToxicity studies required for each leachableNo study required for change of source since the MOC is sameThere will be no surprises in stability studies


CHALLENGES:

To achieve methods for very low levels of AET (e.g. in ppb levels for Large Volume Parenteral)To distinguish between the Drug Product peaks & Leachable peaks in case of Complexpeaks & Leachable peaks in case of Complex drug products (e.g. Oncology products)To select a Reference compound that will reduce the gap between RRF’sTo address the possible leachables in case of absence of info from supplierabsence of info from supplier

THANK YOU

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